Mitogen-activated protein kinases (MAPKs) are members of conserved signal transduction pathways that activate transcription factors, translation factors and other target molecules in response to a variety of extracellular signals. MAPKs are activated by phosphorylation at a dual phosphorylation motif with the sequence Thr-X-Tyr by mitogen-activated protein kinase kinases (MAPKKs). In higher eukaryotes, the physiological role of MAPK signaling has been correlated with cellular events such as proliferation, oncogenesis, development and differentiation. Accordingly, the ability to regulate signal transduction via these pathways could lead to the development of treatments and preventive therapies for human diseases associated with MAPK signaling, such as inflammatory diseases, autoimmune diseases and cancer.
In mammalian cells, three parallel MAPK pathways have been described. The best characterized pathway leads to the activation of the extracellular-signal-regulated kinase (ERK). Less well understood are the signal transduction pathways leading to the activation of the cJun N-terminal kinase (JNK) and the p38 MAPK (for reviews, see Davis, Trends Biochem. Sci. 19:470-473 (1994); Cano and Mahadevan, Trends Biochem. Sci. 20:117-122(1995)). The identification and characterization of members of these cascades is critical for understanding the signal transduction pathways involved and for developing methods for activating or inactivating MAPKs in vivo.
Two MAPKKs capable of activating p38 in vitro have been described (see Derijard et al., Science 267:682-685 (1995)). MKK3 appears to be specific for p38 (i.e., does not activate JNK or ERK), while MKK4 activates both p38 and INK. MKK3 and MKK4 also stimulate the phosphorylation of p38 in certain cell lines after treatment with stimuli, such as ultraviolet radiation and NaCl. However, a stronger and more specific in vivo stimulator of p38 phosphorylation would have greater utility in therapeutic methods.
Accordingly, there is a need in the art for improved methods for modulating p38 activity and related enzymes or kinases in vivo, and for treating diseases associated with the p38 signal transduction pathway. The present invention fulfills these needs and further provides other related advantages.